Various compounds having a cyclic or non-cyclic hydrazine, triazine, or tetrazine group are known to have antineoplastic properties. Such compounds include, for example, altretamine, dacarbazine, mitozolomide, procarbazine, temozolomide, and compounds described in U.S. Pat. No. 5,260,291 as having antineoplastic activity. The main degradation reactions for compounds that contain hydrazine, triazine, or tetrazine groups are oxidation and nucleophilic substitution, the latter of which is a well-known reaction in organic chemistry wherein the nucleophile displaces a good leaving group, resulting in an unwanted hydrolysis product.
For example, temozolomide (chemical name: 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide) is a tetrazine derivative known for its anti-tumor effects, and is marketed as TEMODAR®, which is approved for treating adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment, and is also approved for treating adult patients with refractory anaplastic astrocytoma—i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. Temozolomide rapidly hydrolyzes to 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH. TEMODAR® is supplied as a lyophilized powder containing temozolomide, mannitol, L-threonine, polysorbate 80, sodium citrate dihydrate, and hydrochloric acid; and must be kept refrigerated at 2-8° C. until reconstituted. After reconstitution, the product may be kept at 25° C., but only for 14 hours including infusion time.
U.S. Pat. No. 6,987,108 discloses a pharmaceutical formulation comprising temozolomide or a pharmaceutically acceptable salt thereof, at least one aqueous diluent, and at least one dissolution enhancing agent sufficient to substantially dissolve the temozolomide, wherein the dissolution enhancing agent is urea, L-histidine, L-threonine, L-asparagine, L-serine, or L-glutamine. This patent discloses lyophilized formulations of temozolomide which are to be reconstituted with an aqueous diluent before administration. Further, the disclosed formulations require the presence of a dissolution enhancing agent to increase the rate with which temozolomide dissolves.
U.S. Pat. No. 7,786,118 discloses a pharmaceutical formulation comprising temozolomide or a pharmaceutically acceptable salt thereof, at least one aqueous diluent, and L-threonine. The disclosed formulation is reconstituted with an aqueous diluent before administration, and requires the presence of L-threonine as a dissolution enhancing agent that increases the rate with which temozolomide dissolves.
U.S. Patent Application Publication No. 2012/0283304 discloses a temozolomide formulation for parenteral administration that does not require a dissolution enhancing agent and can purportedly be stored below 25° C.
For reasons of product stability, antineoplastic agents are often supplied to clinical practices in lyophilized form. Freeze-dried vials are sometimes stored under refrigerated conditions (e.g., 2-8° C. for TEMODAR®) and reconstituted prior to use.